For women in United States, breast cancer is the most common non-dermatologic cancer and the second leading cause of cancer death. In 2009, an estimated 192 370 new cases of breast cancer were diagnosed and an estimated 40 170 women died from breast cancer (31
). Methods of breast cancer prevention in high risk women have historically been limited to surgical removal of breast. Bilateral mastectomy is an effective method for breast cancer prevention that results in a risk reduction of at least 90% (28
). However, many women would prefer alternatives to such invasive procedures, and less-invasive methods for breast cancer prevention have been investigated. Tamoxifen, for more than a decade, and raloxifene more recently have been recommended for cancer reduction in women at increased risk for breast cancer (29
. Although many women are eligible for intervention with tamoxifen or raloxifene, few women are treated with these drugs (32
). This is because the efficacy of tamoxifen and raloxifene in preventing breast cancer is limited to estrogen receptor-positive tumors; in addition, there is increased risk from these medications for adverse medical conditions, including endometrial cancer, thromboembolic events and vasomotor effects (30
; as well, the recommendations of dosing are different for pre and postmenopausal women, indicating that other methods of prevention must also be explored.
The chemopreventive properties of the plant phytochemical and dietary ingredient curcumin have been extensively investigated in several preclinical animal models, including in breast cancer (6
). For example, Singletary et al. (35
) showed that intraperitoneal administration of free curcumin at the dose of 100mg/kg or 200mg/kg significantly decreased the number of palpable mammary tumors and suppressed the production of mammary adenocarcinomas in Sprague–Dawley rats in a dimethylbenz(a)anthracence-induced model of mammary tumorigenesis. Similarly, Carroll et al. (36
) reported that dimethylbenz(a)anthracence-induced and medroxy-progesterone acetate-accelerated mammary tumors can be delayed and tumor incidence decreased by intraperitoneal injection of free curcumin at a dose of 200mg/kg for 25 days (36
). Nonetheless, a parenteral route for chemoprevention is not a long-term feasible approach in humans, and the doses utilized in rodents would translate into several grams of curcumin intake, further hampering clinical translation.
To improve the systemic bioavailability of curcumin, numerous approaches have been undertaken. These approaches involve, but are not limited to, the use of adjuvants such as piperine that interfere with glucuronidation (37
), liposomal curcumin and phospholipid complexes (38
, and the use of water-soluble structural analogs of curcumin (40
). Our laboratory was one of the first to synthesize a nanoparticle formulation of curcumin in 2007 (41
) and has since applied NanoCurc in spontaneously metastatic models of pancreatic cancer (22
). Despite enabling widespread tissue distribution (including crossing the blood-brain-barrier) (26
) and circumventing the need for noxious excipients, NanoCurc is not amenable to oral absorption. Therefore, NanoCurc is not suitable for chemoprevention using the oral route of administration.
In this study, we wed two innovative strategies devised by our group—the use of i.duc injection of chemotherapeutics and nano-encapsulation of curcumin enabling its solubility in aqueous media—in order to develop a novel approach toward chemoprevention of breast cancer. Although i.duc administration of agents is still in its infancy, there is an emerging acceptance among breast cancer clinicians for using this route of administration (42
). The rationale for these clinical studies sprouts from preclinical data generated in 2006 in our laboratory using the MNU-induced mammary carcinoma model in rats (3
) and more importantly, from the recent completion of a Phase I trial demonstrating feasibility of the i.duc route in patients (4
). In our current study, we confirmed that i.duc administration of nano-encapsulated or the free curcumin significantly reduces the incidence of mammary tumors compared with control rats, and the protection effects are comparable with what is observed with administration of ‘mega’ amounts of the free drug (200mg/kg or 30–40mg per rat) through the oral route. Although the absolute frequency of ‘breakthrough’ tumors are not statistically distinct between i.duc NanoCurc and i.duc free curcumin cohorts, the former demonstrate significantly smaller size of tumors that do occur, supporting the contention that i.duc NanoCurc breakthrough tumors may be more resectable. Of note, whole mount and histopathological examination of the i.duc NanoCurc-treated breast tissues demonstrated no differences between treated and control groups in ductal histology and periductal inflammation, an important distinction from that observed using chemotherapeutics (3
. This observation engenders the hope that patients receiving i.duc NanoCurc will have sufficient preservation of resident stem cells in the terminal ducto-lobular units to enable rapid repopulation of any ductal epithelium. The absence of histopathological abnormalities is of particular important as many at-risk patients are probably of reproductive age.
Multiple mechanisms of action have been proposed for the anticancer effects of curcumin, but none are probably as seminal as its inhibition of NFκB activity (43
). NFκB is a critical transcription factor that is involved in a wide range of physiological and pathological cellular responses, from cell survival to chemoresistance to decreased apoptosis. In this study, we assessed NFκB activity using a surrogate quantitative measure of nuclear p65 localization and observed downregulation compared with control rats in all three treatments cohorts in Prevention Study 2, with the i.duc NanoCurc arm showing a statistically significant decrease. It is important to note that NFκB is not the only signaling pathway or molecule altered by curcumin, and Aggarwal and colleagues have elaborated a large number of intracellular targets such as cyclo-oxygenase COX-2, vascular endothelial growth factor, STAT3, and Akt, among others (43
. This might explain why the oral free curcumin cohort demonstrated comparable reduction in tumor incidence despite the somewhat attenuated NFκB downregulation observed in mammary epithelium.
We also performed a pilot pharmacokinetic analysis in Sprague–Dawley rats administered i.duc curcumin (either NanoCurc or free curcumin dissolved in corn oil) and compared the circulating levels with that observed upon an equivalent dosing of NanoCurc intraperitoneally. These studies confirmed the prior observations from our group that agents administered through the i.duc route result in minimal peripheral spillover. This data should ameliorate concerns about potential systemic side effects on visceral organs from either curcumin (albeit a safe dietary ingredient) or the delivery vehicle itself (polymer nanoparticle). The lack of toxicity is further reiterated by the complete absence of local cutaneous side effects (excoriation, hair loss) as shown in Supplementary Figure 1
, available at Carcinogenesis
Online. Although these observations will need validation in clinical studies, the preclinical data provides encouraging signals to that effect.
In summary, this study suggests the feasibility of combining NanoCurc formulation with an i.duc approach as a novel strategy for chemoprevention of breast cancer in a well-established chemical carcinogenesis model. As a dietary ingredient used for centuries, curcumin provides a reasonable alternative to cytotoxic compounds as a ‘gentle’ agent for chemoprevention, likely amenable to repeat injections over a longer time frame. Additional studies are required to confirm the efficacy of this formulation in experimental models of carcinogenesis.