Abstract
Down-regulation of the gap junction protein connexin26 (Cx26) is an early event following breast cancer onset and has led to Cx26 being classically described as a tumor suppressor. Interestingly, mutations in theCx26 gene (GJB2) reduce or ablate Cx26 gap junction channel function and are the most common cause of genetic deafness. It is unknown if patients with loss-of-function GJB2 mutations have a greater susceptibility to breast tumorigenesis or aggressive breast cancer progression. To investigate these possibilities, 7, 12-dimethylbenz[α]anthracene (DMBA)-induced tumor development was evaluated in BLG-Cre; Cx26fl/fl mice expressing Cre under the β-Lactoglobulin promoter (Cre+) compared to Cx26fl/fl controlmice (Cre-) following pituitary isograft driven Cx26 knockout. A significantly increased number of DMBA-treated Cre+ mice developed primary mammary tumors, as well as developed multiple tumors, compared to Cre- mice. Primary tumors of Cre+ mice were of multiple histological subtypes and had similar palpable tumour onset and growth rate compared to tumors from Cre- mice. Lungs were evaluated for evidence of metastases revealing a similar percentage of lung metastases in Cre+ and Cre- mice. Together, our results suggest that loss of Cx26 predisposes the mammary gland to chemically induced mammary tumour formation which may have important implications to patients with GJB2 mutations.
Highlights
Breast cancer is the most frequently diagnosed cancer affecting women in the world [1]
Cre- and Cre+ mice were treated with DMBA/oil either after (Group 1) or before (Group 2) Cx26 knockout, and mice were evaluated for palpable tumour onset and number of tumors
When comparing Cre- and Cre+ mice in which 3 months had passed before Cx26 knockout, DMBA-treated Cre+ mice had a significantly (p < 0.0001, logrank test) lower number of mice that remained tumour free compared to Cre- mice over the duration of the experiment (Figure 2A)
Summary
Breast cancer is the most frequently diagnosed cancer affecting women in the world [1]. These perplexing reports highlight the need for additional studies, in vivo, to clarify the role of connexins throughout the progression of breast cancer from tumour onset to metastasis In this pursuit, we recently demonstrated that Cx43 had a critical role in suppressing metastasis to the lungs in a genetically-modified mouse model where Cx43 function was greatly reduced [21]. The 35delG mutation is by far the most common and results in the premature truncation of Cx26 and complete systemic loss of channel function, thereby acting like a knockout in the context of gap junction channel activity [23] Whether this patient cohort is more or less susceptible to breast tumor onset and progression could have profound clinical implications [23]. We hypothesized that low levels of Cx26 within the mammary gland would predispose the mammary gland to the onset of tumors and increase tumour progression and incidence of metastases
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
